M2 macrophages confer resistance to 5-fluorouracil in colorectal cancer through the activation of CCL22/PI3K/AKT signaling

M2 macrophages confer resistance to 5-fluorouracil in colorectal cancer through the activation of CCL22/PI3K/AKT signaling Chen Wei,1–4 Chaogang Yang,1–4 Shuyi Wang,1–4 Dongdong Shi,1–4 Chunxiao Zhang,1–4 Xiaobin Lin,1–4 Bin Xiong1–41Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, People’s Republic of China; 2Department of Gastric and Colorectal Surgical Oncology, Zhongnan Hospital of Wuhan University, Wuhan 430071, People’s Republic of China; 3Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan 430071, People’s Republic of China; 4Hubei Cancer Clinical Study Center, Wuhan 430071, People’s Republic of ChinaBackground: M2 macrophages are crucial components of tumor microenvironment that frequently associated with the resistance of therapeutic treatments in human cancers, but their role in the chemosensitivity of colorectal cancer (CRC) to 5-fluorouracil (5-FU) is still obscure.Methods: In our study, we clarified the biological functions of M2 macrophages and their mechanism on the chemosensitivity of CRC cells to 5-FU. Then, we analyzed the correlation between CCL22 and CD68+, and CD163+, tumor-associated macrophages (TAMs), and further elucidated the prognostic value of CCL22 and CD163+, M2 macrophages in clinical CRC samples.Results: M2 macrophages decreased the inhibitory effect of 5-FU on CRC cells migration and invasion by secreting CCL22, and declined the apoptosis induced by 5-FU. Treated with a neutralizing anti-CCL22 antibody destroyed these effects. We further illuminated that M2 macrophages regulated 5-FU resistance of CRC cells through epithelial-mesenchymal transition (EMT) program, PI3K/AKT pathway, and caspase-mediated apoptosis. Clinically, CCL22 was found to have elevated expression in CRC tissue samples, and was positively associated with CD163+, TAMs. Furthermore, the patients with higher CD163+, M2 macrophages and higher expression of CCL22 in CRC tissues had a lower overall survival (OS) rate compared with lower ones.Conclusion: Our findings indicate that M2 macrophage regulated 5-FU-mediated CRC chemoresistance via the EMT program, PI3K/AKT pathway, and caspase-mediated apoptosis by releasing CCL22.Keywords: M2 macrophages, colorectal cancer, 5-fluorouracil, chemotherapy resistance, CCL22